Monoamine oxidase inhibitors (MAOIs) increase the PRL response to TRP106 and the cortisol response to 5-HTP107 in depressed patients suggesting they may increase 5-HT1A/5-HT2 receptor function but more specific challenge data are unavailable. Antidepressants which lack both 5-HT and noradrenaline reuptake inhibition such as mianserin and trazodone do not enhance the PRL response to TRP108,109 indicating that this is not a universal property of antidepressant drugs. Nefazodone, related to trazodone and with a similar pharmacology, increases PRL concentrations and temperature when given acutely, an action attributed to its metabolite mCPP.110 Chronic treatment with nefazodone results in decreased responses to acute nefazodone challenge suggesting decreased 5-HT2C receptor sensitivity111 which is similar to the blunted responses to mCPP challenge seen following repeated mCPP administration.112
Lithium has antidepressant properties and has been investigated in a number of studies. PRL responses to intravenous TRP are increased following acute and chronic treatment in normal volunteers113,114 although no effect is seen on GH. This is a specific effect on 5-HT-mediated PRL release as PRL responses to dopamine blockade are not altered by lithium treatment.113 In depressed patients an acute enhancement of the PRL response returns to baseline after three weeks of lithium treatment in one study115 but sustained enhancement is seen in another in treatment-resistant patients on antidepressants,116 correlating with clinical response in those who improved but not in non-responders. Lithium treatment also produces a non-significant increase in the PRL response to another presynaptic 5-HT challenge, clomipramine,117 although the receptors mediating the response are not known. On balance this indicates enhanced function of 5-HT1Areceptor-mediated pathways. However, lithium does not alter 5-HT1A receptor sensitivity as measured by PRL, GH, cortisol and temperature responses to gepirone after 7 days treatment in normal volunteers118 indicating a presynaptic mechanism independent of any alteration in 5-HT1A autoreceptor function. Lithium might be expected to reduce 5-HT2 receptor function because of its inhibitory effects on the phosphatidyl inositol second messenger system linked to 5-HT2 receptors.119 However, lithium treatment is reported both to enhance the cortisol response to 5-HTP in depressed patients107 and to have no effect, or a trend to reducing, the PRL response to d-fenfluramine in normal volunteers120 and depressed patients on clomipramine30 leaving open its overall effect on 5-HT2 function.
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